Receptors coupled to heterotrimeric GTP-binding proteins (G-proteins) are integral membrane proteins involved in the transmission of signals from the extracellular environment to the cytoplasm. A variety of external stimuli, including neurotransmitter, hormones, phospholipids, and growth factors, can activate the G-protein coupled receptors (GPCRs). Therefore, the G-protein coupled receptors represent important specific targets for a variety of human diseases, ranging from the control of blood pressure, allergic response, kidney function, and hormonal disorders, and neurological diseases to human cancers. Most recently, we have identified a novel human prostate-specific G-protein coupled receptor (PSGR). Although human PSGR shares sequence homology with other GPCRs in the seven putative transmembrane domains, the expression of PSGR is highly restricted to the epithelial cells of human prostate gland, not in any other human tissues. PCR and Matched Normal/Tumor Tissue Array study shows significant over-expression of PSGR mRNA in prostate tumor tissues. In this grant proposal, we will test the hypothesis that PSGR is a prostate-specific G-protein coupled receptor and a potential molecular target in human prostate cancers. Two specific aims are proposed in our study: First, we will develop fully human antibodies against human prostate-specific G-protein coupled receptor (PSGR) using a highly complex human pACT2-scFv library. Second, we will determine the potential roles of PSGR as a molecular target in prostate cancers using human PSGR antibodies. We will also investigate the possibility of adding a toxin (or a prodrug) to the antibody and test the hypothesis that the antibody-toxin fusion proteins can directly and specifically bind to and kill the PSGR over-expressing prostate cancer cells. The long-term benefits of the proposed research are the potential of the human anti-PSGR antibodies as agents in the treatment of human prostate cancers and PSGR receptor as a molecular target in human prostate cancer therapy.